N-(3-hydroxy-2-ketopropyl)-p-aminobenzoate compounds and their preparation



2,737,524 Patented Mar. 6, 1956 United States Patent "ice aromaticnuclei are represented by one or more simple hexagons. 2,737,524 Thecompounds of the invention are of particular value as intermediates inthe preparation of certain compounds referred to broadly in the art asfolic acids. Thus, as described and claimed in U. S. Patent 2,558,711,diethyl N-(N-(3 hydroxy 2 ketopropyl) N (p toluenesul- Kala a Mich. andStanley Rolfsml, Malfillsfonyl)-paminobenzoyl)-glutamate, which can bepre Ville, t0 Tl le pi Qompany, Kala pared by the method of the presentinvention, can be mazoo, Mich a corporation of Michigan condensed with2,4,5-triamino-6-hydroxypyrimidine to No Drawing. Application October30, 1952, form dlethyl y Y- -p y Serial 317,316 methyl) N (ptoluenesulfonyl) p aminobenzoyl)- glutamate. The latter compound, upontreatment with m (CL hydrogen bromide in an aliphatic acid medium, andin the 15 presence of a bromine acceptor to prevent bromination of thebenzene nucleus of the aminobenzoic acid residue,

according to the method described and claimed in U. S. compounds,particularly to N-(3-hydroxy-2-ketopropy l- Patent 2,562,222, and aftersubsequent hydrolysis of the p-aminobenzoate compounds, and to a methodfor them aster groups, is converted to P P appllcatlon 1S acontlnuatlon'm'part 0 6-pteridyl) methyl) p aminobenzoyl) glutamic acidof application Serial No. 41,889, filed July 31, 1948, now(pteroylglutamic acid) generally recognized, e the S- Patfint 2,625,561glutamic acid'residue has the same configuration as l(+)- The N Y Y P PY)'P' glutamic acid, as being identical with theL. casei factor compoundsof the invention have the generic formula or vitamin B0 f liver. w 3-h dz. 000R ketopropyl)-p-aminobenzoyl)-glutamic acid is condensed H O CH2O0 C O (NHCBHCHZCEHC with 2,4,S-triamino-6-hydroxypyrimidine, pteroylglutamic J acid 1s formed dlrectly without the necessity of splitting a JVI sulfonyl radical from the product with hydrogen bromide or ofhydrolyzing ester groups. In similar fashion, other e p py )r o CompoundN-(3-hydroxy-2-ketopropyl)-p-aminobenzoate compounds wherein R is amember of the group consisting of hydroof the invention can be condensedwith 2,4,5-triamino-6- gen and the alkyl radicals, n is a member of thegroup hydroxypyrimidine to form the corresponding 2-amino-4- consistingof zero and the positive integers 1 to 7, inhydr0Xy-6-pteridyl compoundsof the folic acid type.

N-(3-HYDROXY-2-KETOPROPYL)-p-AMINOBENZO- ATE COMPOUNDS AND THEIRPREPARATION David I. Weisblat, Galesburg, and Barney J. Magerlein,

This invention relates to certain hydroxyketopropyl C O 0 R XOHzCHOHCHPITTQC O (NHHCHaCHzC O)..OR

aryl-S 02 Q I N-(3-halo-2-hydroxypropy1)-p-aminobenzoate compound l C rO a O O 0 B C 0 O R XOHzCOCH -N CQ(NH(HCH;O H=C 0) ,.0R. X-CH COCHrNHCONHHCHaCHzC O )n0R' aryl- O 2 H Br I II IVN-(3-ha1o-2-ketopropyl)-p-aminobenzoate compoundN-(3-halo-2-ketopropyl)-p-aminobenzoate compound (non-arylsulfonyl) lhydrolysis l hydrolysis H0 SE20 0 UHF-$00 O (NHlHOHzCHaC O),.O R HO-O HOOCHr-NHOC 0 (NHHCHaCHrC 0),.O R

y 2 III V N-(3-hydroxy-2-ketopropyl)-p-aminobenzoate compound (wherein ZN-(3-hydroxy-2-ketopropyl)-p-amlnobenzoate compound of FormulaVl=arylsulfonyl) (wherein Z of Formula Vl=hydrogen) elusive, and Z is amember of the group consisting of hy- The N (3 hydroxy2-ketopropyl)-p-aminobenzoate drogen and the arylsulfonyl radicals.compounds of the invention wherein Z of the Formula VI In the naming ofcompounds of the invention and of is an arylsulfonyl radical areprepared readily, as shown the other compounds mentioned herein whenboth a in the accompanying reaction chart wherein R andn have gutamicacid residue and a p-aminobenzoic acid residue the values givenpreviously and wherein X is a member of are included in the molecule,the nitrogen atom of the the group consisting of chlorine, bromine andiodine, by gutamic acid residue is, for convenience, herein referredhydrolyzing an N-(3-halo-2-ketopropyl)-p-aminobenzoate to by the symbolN' and the nitrogen atom of the pcompound (II) to replace the halogenwith an hydroxyl aminobenzoic acid residue is referred to by the symbolradical, the process being carried out in the case of esters N. Asindicated by the generic formula given, comunder conditions to replacethe halogen with hydroxyl pounds containing more than one glutamic acidor ester without hydrolyzing the ester radicals or so as to hydroresiduecontemplated by the invention are those wherein Iyze the lattersimultaneously with the removal of the only the gamma-carboxyl groupsare involved in the pephalogen, if desired. Compounds of the inventionwheretide linkages. In the structural formulae given herein, -in Z ofthe generic Formula V1 is hydrogen, i. e. 'compounds having the FormulaV in the accompanying reaction chart, are prepared conveniently from anN-(3- halo-2-ketopropyl)-p-aminobenzoate compound (II), wherein Z ofFormula VI is an arylsulfonyl radical, by first splitting thearylsulfonyl radical from the molecule by treating the compound withhydrogen bromide according to the method of U. S. Patent 2,562,222. Thenonarylsulfonyl N (3 halo-2-ketopropyl)-p-aminobenzoate compound (IV)thus produced can then be hydrolyzed in the same manner as theN-(3-halo-2-ketopropyl)-paminobenzoate compound (II) having the nitrogenprotected with an arylsulfonyl radical. Both the arylsulfonyl andnon-arylsulfonyl N (3 hydroxy 2-ketopropyl)-paminobenzoate compoundshaving the Formulae III and V, respectively, which are esters can behydrolyzed, using conventional procedures, to the corresponding acidsand the acids themselves can be esterified, using conventionalprocedures, to form the corresponding esters. The replacement of halogenwith hydroxyl in both acid and ester compounds can be carried out usingsubstantially the same procedure. The compounds having the Formulae IIIand V in the accompanying chart together constitute the compounds of theinvention having the Formula VI given previously.

The hydrolysis of both the arylsulfonyl and the nonarylsulfonyl N (3halo-2-ketopropyl)-p-aminobenzoate compounds (II) and (IV) to thecorresponding arylsulfonyl and non-arylsulfonylN-(3-hydroxy-2-ketopropyl)- p-aminobenzoate compounds (III) and (V) canbe carried out conveniently by treating the halogen-containing compoundwith approximately one chemically equivalent proportion of an aqueous oralcoholic alkali, such as aqueous barium carbonate, dilute aqueous oralcoholic sodium hydroxide, or aqueous or alcholic potassium carbonate.The reaction is carried out conveniently by stirring a mixture of thereactants and the medium at ordinary room temperature for from one toseveral hours. When desired to avoid excessive hydrolysis of estergroups in the compounds, soluble alkalies are preferably added to themixture at approximately the rate at which they are consumed. As notedpreviously, however, ester groups when present can be hydrolyzedsimultaneously with the replacement of the halogen with hydroxyl. Insuch case at least one additional chemically equivalent proportion ofalkali is used for each ester group present and less care need be takenin carrying out the reaction than is the case when it is desired toleave the ester groups undisturbed. In the case of hydrolysis ofhaloketo compounds which are acids, it is, of course, necessary to useat least an additional chemically equivalent proportion of alkali foreach carboxy group present in the molecule. Here, also, less care needbe taken in carrying out the hydrolysis than is desirable when a halogenis to be replaced with hydroxyl without disturbing ester groups whichmay be present. 7

Following the hydrolysis reaction the N-(3-hydroxy-2-ketopropyl)-p-aminobenzoate compound can be recovered from the reactionmixture in any convenient way. In the case of hydroxyketo esters, themixture can be poured into water and extracted with a suitablewaterlmmiscible solvent for the ester, such as ether, benzene or thelike. In the case of hydroxyketo acids, the reactlon mixture can bepoured into water, alkalized if nece sary, and the alkaline solutionextracted with ether or other suitable Water-immiscible liquid and theextract discarded. The extracted solution can then be neutralized with amineral acid and again extracted with ether or other suitable solventfor the hydroxyketo acid. In either case, the extract of the desiredcompound thus obtained can be evaporated to remove the solvent andhydroxyketo compound obtained in a form suitable for most purposes.Purification can frequently be effected by recrystallization of theproduct from a suitable solvent.

Purification can also .be effected using Girards reagent P. or T. toyield the hydroxyketo compounds, usually in solid form.

The N-(3-halo-2-ketopropyl)-p-aminobenzoate compound (II) used asstarting material in the process of the invention can be prepared asdescribed in the parent application and as described and claimed inconcurrently filed copending application Serial No. 317,815, now U. S.Patent 2,674,618, which is also a continuation-in-part of the parentapplication Serial No. 41,889, new U. S. Patent 2,625,562, by oxidizingan N-(3-halo-2-hydroxypropyl)-p-aminobenzoate compound (I) with chromicanhydride in an inert water-soluble solvent. A solution of the N (3 halo2 hydroxypropyl)-N-(arylsulfonylp-aminobenzoate compound (I) and ofchromic anhydride in acetic acid can be prepared and allowed to standfor several hours at from about 0 degrees to about 30 degrees C. orsomewhat higher, or the N-(3-halo-2-hydroxypropyl) -N-(arylsuifonyl) paminobenzoate compound can be added gradually to a solution of chromicanhydride in acetic acid. Reaction usually occurs smoothly at or dinaryroom temperature, or somewhat below, but the mixture can, in certaininstances, be warmed gently, if desired.

The reaction is usually substantially complete in from one to severalhours and the N(3-halo-2-ketopropyl) N-(arylsulfonyl)-p-aminobenzoatecompound can be recovered by diluting the reaction mixture with waterand extracting the diluted mixture with ethyl acetate, ether or othersuitable solvent. The extract is dried after washing with water or withaqueous sodium bicarbonate, depending upon whether it contains carboxyor carboxylic ester groups, and the ether or other solvent thendistilled. The N- 3-halo-2-ketopropyl) -N- arylsulfonyl)-p-aminobenzoate compound is thus generally obtained as a solid residuewhich is usually sufliciently pure for further use but which can, ifdesired, be purified further by crystallization from dilute ethanol orin other convenient manner. Purification can also be effected usingGirards reagent P. or T. to yield the halolieto compounds usually insolid form.

The arylsulfonyl radical can be split readily from anN-(3-halo-2-ketopropyl) N (arylsulfonyl)-p-aminoben zoate compoundhaving the Formula II according to the method mentioned previously toform an N-(3-halo-2- ketopropyl)-p-aminobenzoate compound having theFormula III usually without isolating the arylsulfonyl-containingcompound from the acetic acid reaction mixture, if desired. The reactionis carried out conveniently by mixing the arylsulfonyl compound,hydrogen bromide and a bromine acceptor, such as phenol, catechol ornaphthol, in an anhydrous aliphatic acid medium, usually at ordinaryroom temperature. Several molar proportions of hydrogen bromide areusually employed. After standing for a sufiicient length of time,usually for from a few minutes to a few hours, the mixture can be pouredinto ether or petroleum naphtha and the hydrobromide of the free aminerecovered by filtering.

The N (3-halo-2-hydroxypropyl)-N-(arylsulfonyl)-paminobenzoate compounds(I) from which the N-(3-halo- 2-ketopropyl)N-(arylsulfonyl) paminobenzoate compounds (II) can be prepared by oxidation with chromicacid, can, themselves, be prepared in any convenient way. One such way,described in co-pending application Serial No. 41,884, now U. S. Patent2,629,733, and described and claimed in co-pending application SerialNo. 317,813, which is a continuation-in-part thereof, comprises reactingan epihalohydrin, i. e. epichlorohydrin, epibromohydrin orepiiodohydrin, with a p-aminobenzoate compound having the followingFormula VII ar l-dO p-Aminobenzoate compound wherein R and n have thevalues given previously. Certain of the latter compounds and theirpreparation are described and claimed in co-pending application SerialNo. 41,888, now U. S. Patent 2,697,719. The N-(3-halo- 2-hydroxypropyl)N (arylsulfonyl) p aminobenzoate compound is formed directly as a resultof the reaction and can be isolated in any convenient manner.

As indicated by the generic Formula VI, N-(3-hydroxy- Z-ketopropyl) paminobenzoate compounds containing more than one glutamic acid or esterresidue contemplated by the invention are those wherein only thegammacarboxyl groups are involved in the peptide linkages, such as theresidues derived from N'-(p-aminobenzoyl)- gamma-glutamylglutamic acid,and the like. Preferred compounds of the invention are those wherein nrepresents the integer l, i. e. those containing one glutamic acid orester residue, and the invention will be described with particularreference thereto.

Compounds similar to, or identical with, those of the folic acid groupmade by using compounds of the invention as intermediates, such aspteroylglutarnic acid and pteroyl-gamma-glutamyl gamma glutamylglutamicacid, which are of greatest value as measures by their biologicalactivity against Lactobacillus casei or Streptococcus fecalis R., arethose wherein the glutamic acid residues possess the same configurationas l(+)-glutamic :acid. However, the invention also contemplatescompounds having the dextro configuration as well as racernic mixtures.

N-(3-h y d r o x y-2ketopropyl) -p-aminobenzoate compounds wherein Z ofthe generic Formula VI represents an arylsulfonyl radical, are ofparticular value because of the protection afforded the aromatic aminogroup by the arylsulfonyl group. Compounds having the amino group thusprotected are often not subject to decomposition and the formation ofby-products when employed as a reactant, e. g. when condensed with2,4,5-triamino- 6-hydroxypyrimidine, to nearly the same extent as arecompounds in which the aromatic amino group is unprotected. Followingthe carrying out of a reaction using anN-(3-hydroxy-2-ketopropyl)-p-aminobenzoate compound containing such anarylsulfonylamino group, the arylsulfonyl radical can be split readilyfrom the molecule formed, as mentioned previously, by treating thecompound with hydrogen bromide in an aliphatic acid medium and in thepresence of a' bromine acceptor.

Although the invention is described in the case of arylsulfonylcompounds with particular reference to ptoluenesulfonyl compounds, it isunderstood that the invention contemplates compounds and intermediatescontaining other arylsulfonyl radicals, such as the otoluenesuifonyl,benzenesulfonyl, and naphthalenesulfonyl radicals as well as manyothers. Arylsulfonyl radicals having substituents, suclras chlorine,bromine, or a nitro group, on the aromatic nucleus can also be usedprovided only that the substituent is nonreactive under the reactionconditions. The preferred arylsulfonyl radical is the p-toluenesulfonylradical because the compounds formed are generally well definedcrystalline solids and because it has been found that higher yields ofamines are often formed when splitting a p-toluenesulfonylamino compoundthan when splitting certain other arylsulfonyl derivatives of the sameamino compound. it should be mentioned, furthermore, that the methodinvolved in the present invention can be carried out and thecorresponding final compounds prepared using starting compounds whereinthe arylsulfonyl group is replaced by an alkylsulfonyl, aralkylsulfonylor cycloalkylsulfonyl group, such as the methanesulfonyl,alpha-toluenesulfonyl or cyclohexylsulfonyl radicals, respectively.

Although benzoic acid ester or glutamic acid ester residues present incertain of the compounds of the invention can comprise any alkyl ester,such as the methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl,amyl, .lauryl, dodecyl and many other esters, the preferred ester 6 isthe ethyl ester due to matters of convenience and economy.

Although the invention is directed particularly, in case of esters ofthe aminobenzoic acid and glutamic acid residues, to alkyl esters, theprocess of the, invention can also be carried out and correspondingcompounds prepared using other esters, such-as the phenyl, tolyl, xylyl,cyclohexyl, benzyl and many other aryl, aralkyl or cycloalkyl esters.

Certain advantages of the invention are apparent from the followingexamples which are given by way of illustration only and are not to beconstrued as limiting.

Example 1.Ethyl N-(3-chloror2+hydroxypropyl)-N-(ptoluenesulfonyl)-p.-amino ber z0ate A mixture of 5 grams of ethyl N-(p-toluenesulfonyD-p-aminobenzoate and 3.4 milliliters of epichlorohydrin was heated atdegrees C. and 2 drops of pyridine added. A vigorous action ensued andafter 5 minutes the mixture was cooled, dissolved in 50 milliliters ofethanol and treated three times with decolorizing carbon. The ethyl N (3chloro 2 hydroxypropyl) N (p toluenesulfonyl) -p-aminobenzoate whichremained upon volatilization of the ethanol and excess epiehlorohydrinin vacuo was usd in subsequent reactions without further purification.

In similar manner methylN-(3-chloro-2-hydroxypropyl)-N-(o-toluenesulfonyl)-p-aminobenzoate,n-butyl N- (3 chloro 2 hydroxypropyl) N (betanaphthalenesulfonyl)-p-aminobenzoate, and dodecyl N-(3-chloro-2-hydroxypropyl) N (p chlorobenzenesulfonyl) paminobenzoate are obtainedby substituting an equimolar proportion of methylN-(o-toluenesulfonyl)-p-aminobenzoate, n-butylN-(beta-naphthalenesulfonyl)-p-arninobenzoate, and dodecylN-(p-chlorobenzenesulfonyl)-p-aminobenzoate, respectively, for the ethylN-(p-toluenesulfony l) p-aminobenzoate in the foregoing procedure.

By using equi-molar proportions of epibromohydrin or of epiiodohydrin inplace of epichlorohydrin in the foregoing procedure there are obtainedethyl N-(3 bromo-2- hydroxypropyl) N (p toluenesulfonyl) p aminobenzoateand ethylN-(3-iodo-2-hydroxypropyl)-N-(ptoluenesulfonyl)-p-aminobenzoate,respeetively.

Example 2.-Diethyl N'-(N-(3-chl0r0-2-hydr0xypr0pyl)- N p-toluenesulfonyl-p-amin0benzoyl -gluta mate A mixture of 2.85 grams of diethylN-(N-(p-toluenesulfonyl)-p-aminobenzoyl)glutamate and 1.1 grams ofepichlorohydrin was agitated at 135 degrees C. Two drops of pyridinewere added and agitation at 135 degrees C. was continued for 5 minutes.The excess epichlorohydrin was volatilized under reduced pressure. Theresidue which consisted of diethyl N'.-(N-(3-chloro- 2-hydroxypropyl) N(p toluenesulfonyl) p aminobenzoyl)-glutamate was used in subsequentexperiments without further purification.

When an equi-molar proportion of dimethyl ;N-(N- (benzenesulfonyl)p-aminobenzoyl) glutamate, diisobutyl N (N (betanaphthalenesulfonyl)-praminobenzoyl) glutamate, or di-dodecylN'-(N-(o-toluenesulfonyl)-p-aminobenzoyl)glutamate, is substituted forthe diethyl N'- (N- (p-toluenesulfonyl) -p-aminobenzoyl) -glutamate inthe above procedure, there are obtained dimethyl N (N (3 chloro 2hydroxypropyl) N (benzenesulfonyl)-p-aminobenzoy1)glutamate,di-iso-butyl N- (N (3 chloro 2 hydroxypropyl) N (betanaphthalenesulfonyl)-p-aminobenzoyl)-g1utamate and .di-dodecylN-(N-(3-chloro-2-hydroxypropyl)-N-(o-toluenesulfonyl) -p-aminobenzoyl)glutamate, respectively.

By using equi-molar proportions of epibromohydrin or of epiiodohydrin inplace of epichlorohydrin in the foregoingprocedure there are obtaineddiethyl N'-(N-.(3- bromo 2 hydroxypropyl) N (p toluenes-ulfonyl)-p-aminobenzoyl)eglutamate and diethyl Nt-(N-(3-iodo- 2 hydroxypropyl) N(p toluenesulfonyl) p aminobenzoyl) glutamate, respectively.

Example 3.Ethyl N-(3-chl0ro-2-ket0propyl)-N-(ptoluenesulfonyl)-p-aminobenzate The crude oily ethyl N-(3-chloro-2-hydroxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoate prepared from 30 grams of ethylN-(p-toluenesulfonyl)-p-aminobenzoate and an excess of epichlorohydrinwas dissolved in 150 milliliters of acetic acid and a mixture of 12grams of sodium dichromate, 10 milliliters of sulfuric acid, 45milliliters of water and 60 milliliters of acetic acid was added over aperiod of three hours while maintaining the mixture at 5 degrees C.After stirring for an additional three hours, the oxidation mixture wasdiluted with water and extracted with ether. The ethereal extract waswashed with sodium bicarbonate and the ether distilled. The residue ofethyl N (3 chloro 2 ketopropyl) N (p toluenesul fonyl)-p-aminobenzoatecrystallized from dilute ethanol on prolonged standing. The crystallizedproduct Weighed 5.5 grams and after two crystallizations from diluteethanol, melted at 106 degrees to 113 degrees C Analysis-Calcd. forC19H2005NSC1Z C, 55.7; H, 4.9; CI, 8.7. Found: C, 56.0; H, 4.9; Cl 6.1.

Following the foregoing procedure and using an equimolar proportion ofmethylN-(3-chlor0-2-hydroxypropyl)-N-(o-toluenesulfonyl)-p-aminobenzoate,n-butyl N- (3 chloro 2 hydroxypropyl) N betanaphthalenesulfonyl)-p-aminobenzoate, dodecylN-(3-ch1oro-2-hydroxypropyl) N (p chlorobenzenesulfonyl) paminobenzoate,ethyl N-(3-bromo-2-hydroxypropyl)-N- (p-toluenesulfonyl)-p-aminobenzoateor ethyl N-(S-iodo- 2-hydroxypropyl)-N-(ptoluenesulfonyl)p-aminobenzoate or the corresponding hydroxy acids in place of the ethylN-(3-chloro-2-hydroxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoate thereare obtained methyl N-(3- chloro 2 ketopropyl) N (o toluenesulfonyl)paminobenzoate, n-butyl N-(3-chloro-2-ketopropyl)-N-(beta-naphthalenesulfonyl)-p-amincbenzoate, dodecyl N- (3 chloro 2ketopropyl) N (p chlorobenzenesulfonyl) -p-aminobenzoate, ethyl N- 3-bromo-2-ketopro pyl)-N-(p-toluenesulfonyl)-p-aminobenzoate, ethyl N-(3-iodo-Z-ketopropyl) -N- (p-toluenesulfonyl) -p-aminobenzoate, and thecorresponding keto acids, respectively.

The keto esters thus prepared are hydrolyzed with dilute alkali to thecorresponding keto acids.

Example 4.-Diethyl N (N- (3-chloro-2-ketopropyl) -N (p-toluenesulfonylp-amin obenzoyl -glumma is The oily diethylN'-(N-(3-chloro-2-hydroxypropyl)- N(p-toluenesulfonyl)-p-aminobenzoyl)glutamate prepared from 2.85 grams ofdiethyl N-(p-toluenesulfonyl)- p-aminobenzoyl)glutamate and an excess ofepichlorohydrin was dissolved in milliliters of glacial acetic acid. Amixture of 0.8 gram of chromic anhydride, l8 milliliters of glacialacetic acid and l milliliter of water was added slowly with stirring andcooling. The mixture was allowed to stand at room temperature for 12hours and the acetic acid then volatilized under reduced pressure. Theresidue was taken up in a mixture of water and ether and the layersseparated. The ether layer was washed with water until the washings wereno longer green and then treated with charcoal and dried over anhydrousmagnesium sulfate. Upon distillation of the ether, there remaineddiethylN'(N-(3-chloro-2-ketopr0pyl)-N-(ptoluenesulfonyl)-p-aminobenzoyl)glutamateas a pale yellow viscous oil.

Following the foregoing procedure and using an equimolar proportion ofdimethyl N'-(N-(3-chloro-2-hydroxypropyl)-N-(benzenesulfonyl) paminobenzoyl) glutamate, di-iso-butylN'-(N-(3-chloro-2-hydroxypropyl)-N- (beta naphthalenesulfonyl) paminobenzoyl) glutamate, di-dodecyl N'- (N- 3-chloro-2-hydroxypropyl)-N- (o-toluenesulfonyl) -p-aminobenzoyl) lutamate, diethylN'-(N-(3-bromo-2-hydroxypropyl) N (p toluenesul- 8fonyl)-p-amin0benzoy1)glutamate, diethyl N'-(N-(3-iodo-2-hydroxypropyl)-N-(p-toluenesulfonyl)-p aminobenzoyl)-glutamate orof the corresponding hydroxy acids in place of diethylN-(N(S-chloro-Z-hydroxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoyl)glutamate, there are obtained dimethyl N-(N-(3-chloro-2- ketopropyl)-N(benzenesulfonyl) p aminobenzoyD- glutamate, di-iso-butylN-(N-(3-chloro-2-ketopropyl)- N-(beta-naphthalenesulfonyl)-paminobenzoyl) glutamate, (ii-dodecyl N- (N- (3 -chloro-2-ketopropyl) -N-(otoluenesulfonyl)-p-aminobenzoyl)glutamate, diethyl N-(N(3-bromo-2-ketopropyl)-N (p toluenesulfonyl) paminobenzoyl)-glutamate,diethyl N-(N-(3-iodo-2-ketopropyl)-N-(p-toluenesulfonyl)-p-aminobenzoyl)glutamate, and the corresponding keto acids, respectively.

Example 5.Ethyl N-(3-chl0r0-2-ket0pr0p3 l)-p-amin0- benzoatehydrobromide A mixture was prepared consisting of 0.5 gram of ethylN-(3-chloro-2-ketopropyl)-N-(p toluenesulfonyl) paminobenzoate, 0.235gram of phenol and 5 milliliters of a per cent solution of hydrogenbromide in glacial acetic acid. The mixture was allowed to stand for 2hours at room temperature and then pouredinto milliliters of dry ether.The mixture was filtered and the crystalline residue washed with dryether and then dried. There was obtained 0.07 gram of ethylN-(3-chloro-2- ketopropyl)-p-aminobenzoate-hydrobromide. This product,when condensed with 2,4,5-triamino 6 -hydroxypyrimidine, yielded aproduct having a marked activity for Streptococcus fecalis R.

In entirely analogous fashion and using substantially equi-molarproportions of the respective reactants as used therein, thearylsulfonyl radical is split from methyl N (3 chloro 2 ketopropyl) N (ptoluenesulfonyl)-p-aminobenzoate, n-butyl N-(3-ch1oro-2-ketopropyl) N(beta naphthalenesulfonyl) p aminobenzoate, dodecyl N (3 chloro 2ketopropyl) N (pchlorobenzenesulfonyl) p aminobenzoate, ethyl N- (3bromo 2 ketopropyl) N (p toluenesulfonyl)-paminobenzoate, e t h y lN-(3-i0do-2-ketopropyl) -N-(ptoluenesulfonyl)-p-aminobenzoate, dimethylN-(N-(3- chloro-2-ketopropyD-N (benzenesulfonyl) paminobenzoyl)-glutamate, di-iso-butyl N-(N-(3-chloro-2-ketopropyl) N(beta naphthalenesulfonyl) p aminobenzoyD-glutamate, di-dodecylN'-(N-(3-chloro-2-ketopropyl)-N-(o-toluenesulfonyl)-p aminobenzoyl)glutamate, diethyl N- (N- 3 -chloro-2-ketopropyl) -N-(p-toluenesulfonyl)-p-aminobenzoyl)glutamate, diethyl N-(N-(3-br0mo-2-ketopropyl) N (p toluenesulfonyl) paminobenzoyl)-glutamate,diethyl N'-(N-(3-iodo-2-ketopropyl) N(p-toluenesulfonyl)-p-aminobenzoyl)-glutamate and the correspondingarylsulfonyl acids to form methyl N-(3-chloro-2-ketopropyl)-p-aminobenzoate, nbutyl N (3chloro-2-ket0propyl)-p-aminobenzoate, dodecyl N (3chloro-Z-ketopropyl)-p-aminobenzoate, ethyl N(3-bromo-2-ketopropyl)-p-aminobenzoate, ethyl N-(3-iodo-2-ketopropyl)-paminobenzoate, dimethyl N- (N (3-chloro-2-ketopropyl) -p-aminobenzoyl)glutamate, di-iso-butyl N (N (3-chloro-2-ketopropyl)-p-aminobenzoyl)-glutamate, di-dodecylN'-(N-(3-chloro-2-ketopropyl)-p-aminobenzoyl) glutamate, diethylN'-(N-(3- chloro-Z-ketopropyl) -paminobenzoyl) glutamate, diethyl N(N-(3-bromo-2-ketopropyl)-p-aminobenzoyl)-gluta mate, diethyl N(N-(3-iodo-2-ketopropyl)-p-aminobenzoyl)-gluta1nate and thecorresponding non-arylsulfonyl acids, respectively.

Example 6 .-Ethyl N- (3-hya'r0xy-2-ketr0pr0pyl) -N-(p-toluenesulfonyl)-p-aminobenz0ate One gram of ethyl N(3-chloro-2-ketopropyl)-N-(ptoluenesulfonyl) p aminobenzoate wasdissolved in 20 milliliters of acetone and the solution diluted with 10milliliters of water. One-half gram of barium carbonate was then addedand the mixture stirred overnight at room temperature and then refluxedfor 2.hours. The mixture was then filtered, partially concentrated,refiltered and then concentrated. The thick liquid was dissolved inether, washed with water and again concentrated to a viscous liquid. Theethyl N (3-hydroxy-2-ketopropyl)- N-(p-toluenesulfonyl) -p-an1inobenzoate thus obtained weighed 0.27 gram.

Example 7.--Ethyl N-(3-hydr0xy-Z-ketopropyl)-N-(p-toluenesulfonyl)-p-aminbenz0ate A solution was prepared consisting of0.3 gram of ethyl N (3chloro-Z-ketopropyl)-N-(p-toluenesulfonyl)-paminobenzoate, millilitersof acetone and 3 milliliters of water and 7.5 milliliters of 0.1- normalsodium hydroxide solution was added with gentle agitation at roomtemperature over a period of one hour. The solution was then dilutedwith water and-filtered. Therevwas thus obtained 0.1 gram of solid ethylN- (3 -hydroxy-2-ketopropyl) -N-(p-toluenesulfonyl) p aminobenzoatewhich decomposed over a wide range on heating. The compound wassubsequently condensed with 2,4,5-triaminofi-hydroxypyrimidine to formthe toluenesulfonyl derivative of the ethyl ester of pteroic acid.

Example 8 Following the procedure of Example 6 or of Example 7 andreplacing the ethyl N-(3-chloro-2-ketopropyl)-N-(p-toluenesulfonyl)-p-aminobenzoate with an equi-rnolar proportion ofmethyl N (3 chloro-2-ketopropyl)-N- (o-toluenesulfonyl)-p-aminobenzoate,n-butyl N-(3-chloro Z-ketopropyl)-N-(beta-naphthalenesulfonyl)-p-aminobenzoate, dodecyl N (3 chloro-2-ketopropy1)-N-(p-chlorobenzenesulfonyl) p aminobenzoate, ethyl N-(3-bromo-2-ketopropyl)-N-(p-toluenesulfonyl) p aminobenzoate, ethylN-(3-iodo-2-ketopropyl)-N-(p-toluene sulfonyl)p-aminobenzoate, diethyl N(N-(3-chloro-2- ketopropyl) N (p-toluenesulfonyl)-p-aminobenzoyl)-glutamate, dirnethyl N (N-(3-chloro-2-ketopropyl)-N- (benzenesulfonyl) paminobenzoyle)-glutamate, di-isobutyl N(N-(3-chloro-2-ketopropyl)-N-(betanaphthalenesulfonyl) -p-aminobenzoyl)-glutamate, di-dodecyl N- (N (3chloro-2-ketopropyl)-N-(o-toluenesulfonyl)-paminobenzoyl) glutamate,diethyl N-(N-(3-bromo-2- ketopropyl) N(p-toluenesulfonyl)-p-arninobenzoyl)- glutamate, diethyl N (N-(3-iodo-2-ketopropyl)-N-(ptoluenesulfonyl)-p aminobenzoyl) glutamate,ethyl N- (3-chloro-2-ketopropyl)-p-aminobenzoate, ethyl N (3bromo-Z-ketopropyl) -p-aminobenzoate, ethyl N- 3-iodo-2-ketopropyl)-p-aminobenzoate, diethyl N'-(N-(3-chloro 2-ketopropyl)-p-aminobenzoyl) glutamate, diethyl N'- (N-(3-bromo-2-ketropropyl)-p-aminobenzoyl) glutamate or of diethylN'-(N-(3-iodo-2-ketopropyl)-p-aminobenzoyl)- glutamate, there areobtained methyl N-(3-hydroxy-2- ketopropyl)N-(o-toluenesulfonyl)-p-aminobenzoate, nbutyl N(3-hydroxy-2-ketopropyl)-N-(beta-naphthalenesulfonyl) p aminobenzoate,dodecyl N (3-hydroxy-2- ketopropyl) -N- (p-chlorobenzenesulfonyl)-p-aminobenzoate, ethyl N (3 hydroxy2-ketopropyl)-N-(p-toluenesulfonyl)-p-aminobenzoate, ethyl N(3-hydroxy-2-ketopropyl) N-(p-toluenesulfonyl)-p-aminobenzoate, diethylN' -(N-(3-hydroxy-2-ketopropyl)-N-(p-toluenesulfonyl)-p-aminobenzoyl)glutamate, diethyl N-(N-(3-hydroxy- Z-ketopropyl) N(p-toluenesulfonyl)-p-aminobenzoyl)- glutamate, dimethyl N (N(3-hydroxy-2-ketopropyl)- N (benzenesulfonyl)-p-aminobenzoyl) glutamate,diiso-butyl N (N (3 hydroxy 2 ketopropyl) N N-(beta-naphthalenesulfonyl)p aminobenzoyl) glu tamate, di-dodecyl N'- N- 3-hydroxy-2-ketopropyl -N-(o-toluenesulfonyl)-p-aminobenzoyl) glutamate, diethyl N(N-(3-hydroXy-2-ketopropyl)-N-(p-toluenesulfonyl)-p-aminobenzoyl)-glutarnate, diethyl N-(N-(3-hydroxy-2- ketopropyl) N(p-toluenesulfonyl)-p-aminobenzoyl)- glutamate, ethyl N-(3-hydroxy-2-ketopropyl)-p-aminobenzoate, ethyl N(3-hydroxy-2-ketopropyl)-p-amino benzoate, ethyl N(3-hydroxy-2-ketopropyl)-p-amino- 10 benzoate, diethyl N(N-(3-hydroxy-2-ketopropyl)-paminobenzoyl) glutamate, diethylN-(N-(3-hydroxy-2- ketopropyl)-p-aminobenzoyl)glutamate or of diethylN'- (N (3 hydroxy-Z-ketopropyl)-p-aminobenzoyl)-glutamate, respectively.

Following the procedure of Example 7, but increasing the proportion ofalkali by slightly over one additional chemically equivalent proportionin the case of the aminobenzoates and by slightly more than twoadditional chemically equivalent proportions in the case of theglutamates, and warming the mixture somewhat, the above haloketo estersare each converted to the corresponding hydroxyketo acids.

Example 9.N (3 hydroxy 2 ketopropyl) N (ptoluenesulfonyl) paminobenzdic-acid Eleven milliliters of 0.1 normal sodiumhydroxidesqlution was added at room temperature over a-period of one 7hour to an agitated solution of 0.2 gram of N-(3-chloro-2- ketopropyl)-N- p-toluenesulfonyl -p-aminobenzoic acid in 10 milliliters of acetoneand 8 milliliters of water. The rate of addition was adjusted so thatthe pH of the solution was at all times less than 8.5. Acetone was thendistilled in vacuo from the mixture and the residue extracted withether. Upon drying the ethereal solution and volatilizing the ether,there was obtained a non-crystalline residue ofN-(3-hydroxy-2-ketopropyl)-N-(p-toluenesulfonyl)-p-aminobenzoic acidwhich was used in a subsequent reaction without further purification.

In entirely similar manner each of the haloketo acids falling within thescope of the Formulae II and IV of the reaction chart is converted tothe corresponding hydroxyketo acid by substituting an equi-molarproportion thereof for theN-(3-chloro-2-ketopropyl)-N-(p-toluenesulfonyD-p-aminobenzoic acid inthe foregoing procedure.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is, therefore, to be limited only by thescope of the appended claims.

We claim:

1. The method which includes: hydrolyzing with an alkali a compoundhaving the formula COOB x-onio 0 cut-1 10c o mndnornonzo o ..oR'

COOR' I HO-CHzC O GEM-NCO O (NHOHCHzCHzC 0),.OR"

wherein R, n and Z have the values given.

2. The method of claim 1 wherein R is an alkyl radical, 11 is theinteger 1, X is chlorine and Z is an arylsulfonyl radical.

3. The method of claim 1 wherein R is an alky radical, X is chlorine, nis the integer 1 and Z is an arylsulfonyl radical and the hydrolysis iscarried out using about one chemically equivalent proportion of a dilutewater-- soluble alkali.

4. The method of claim 1 wherein the hydrolysis is. carried out in amedium comprising a water-soluble organic compound.

5. The method of claim 1 wherein the hydrolysis is carried out in amedium comprising a water-soluble ketone.

6. The method which includes: hydrolyzing ethyl N- (3 chloro 2ketopropyl) N (p toluenesulfonyD- p-aminobenzoate with an alkali to formethyl N-(3-hydroxy 2 ketopropyl) N (p toluenesulfonyl) paminobenzoate.

7. The method of claim 6 wherein the alkali is added to the reactionmixture at substantially the rate at which it is consumed.

8. The method which includes: hydrolyzing diethyl N- (N (3 chloro 2ketopropyl) N (p toluenesulfonyl)-p-aminobenzoyl)-glutamate with analkali to form diethyl N (N (3 hydroxy 2 ketopropyl) I(ptoluenesulfonyl) -p-aminobenzoyl) glutamate.

9. The method of claim 8 wherein the alkali is added to the reactionmixture at substantially the rate at which it is consumed.

10. A compound having the formula COOR I no-onic 0 CHrITT- C o Nnoncmomo(me R 12 wherein R is a member of the group consisting of hydrogen andthe alkyl radicals, n is a member of the group consisting of zero andthe positive integer l and Z is a member of the group consisting ofhydrogen and the arylsulfonyl radicals.

11. A compound having the formula C O O-alkyl aryl-SO2 l2. Ethyl N (3hydroxy 2 ketopropyl) N (ptoluenesulronyl) -p-aminobenzoate.

13. N (3 hydroxy 2 ketopropyl) N (p toluenesulfonyD-p-aminobenzoic acid.

14. Diethyl N (N (3 hydroxy 2 ketopropyl)- N (p toluenesulfonyl) paminobenzoyl) glutamate.

15. N (N (3 hydroxy 2 ketopropyl) N (ptoluenesulfonyl -p-aminobenz0yl)-glutamic acid.

No references cited.

1. THE METHOD WHICH INCLUDES: HYDROLYZING WITH AN ALKALI A COMPOUNDHAVING THE FORMULA
 10. A COMPOUND HAVING THE FORMULA